Quantitative flow ratio or angiography for the assessment of non-culprit lesions in acute coronary syndromes, a randomized trial.

BACKGROUND: Patients undergoing percutaneous coronary intervention for acute coronary syndromes often have multivessel disease (MVD). Quantitative flow ratio (QFR) is an angiography-based technology that may help quantify the functional significance of non-culprit lesions, with the advantage that measurements are possible also once the patient is discharged from the catheterization laboratory. AIM: Our two-center, randomized superiority trial aimed to test whether QFR, as compared to angiography, modifies the rate of non-culprit lesion interventions (primary functional endpoint) and improves the outcomes of patients with acute coronary syndromes and MVD (primary clinical endpoint). METHODS: In total, 202 consecutive patients (64 [56-71] years of age, 160 men) with STEMI (n = 69 (34%)), NSTEMI (n = 94 (47%)), or unstable angina (n = 39 (19%)) and MVD who had undergone successful treatment of all culprit lesions were randomized 1:1 to angiography- vs. QFR-guided delayed revascularization of 246 non-culprit stenoses (1.2/patient). RESULTS: The proportion of patients assigned to medical treatment versus percutaneous intervention was not different between groups (angiography group: 45 (45%) vs. QFR: 56 (55%), P = 0.125; relative risk = 0.80 (0.60-1.06)). At 12 months, a primary clinical endpoint event (composite of death, nonfatal myocardial infarction, revascularization, and significant angina) occurred in 24 patients (angiography-guided) and 23 patients (QFR-guided; P = 0.637, HR = 1.16 [0.63-2.15]). None of its components was different between groups. DISCUSSION: QFR guidance based on analysis of images from the primary intervention was not associated with a difference in the rate of non-culprit lesion staged revascularization nor in the 12-month incidence of clinical events in patients with acute coronary syndromes and multivessel disease. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04808310).

TNF-α blockade may lead to improvement of vascular function in psoriasis patients.

Psoriasis is one of the most common chronic inflammatory skin diseases and at the same time a risk factor for cardiovascular disease. Interleukin-17A (IL-17A)-mediated inflammation in psoriasis may lead to vascular dysfunction. This study aimed at investigating whether anti-inflammatory treatment by tumor necrosis factor (TNF)-α blockade alters vascular function in psoriasis patients. A total of 11 patients with psoriasis who underwent treatment with either adalimumab (n = 8) or etanercept (n = 3), 10 healthy control individuals and 14 patients with coronary artery disease (CAD) were included in this study. Treatment response was assessed using the Psoriasis Area and Severity Index (PASI) score. Endothelial reactivity and resting endothelium-dependent vascular tone were assessed by ultrasound measurement of flow-mediated dilation (FMD) and low-flow-mediated constriction (l-FMC), respectively. FMD was slightly impaired in psoriasis patients compared to healthy controls. Anti-TNF-α treatment did not significantly change FMD levels. Psoriasis patients showed a trend towards increased baseline vascular activity compared to healthy controls. Anti-TNF-α treatment significantly improved l-FMC in psoriasis patients. Noteworthy, both FMD and l-FMC in psoriasis patients were comparable to those in patients with CAD; however, an important influence of age differences between the groups or co-existent classical cardiovascular risk factors on FMD and l-FMC cannot be ruled out by our small study. The results suggest that anti-inflammatory treatment with TNF-α blockade improves vascular function in patients with psoriasis, mainly by altering baseline vascular tone. Further studies will be necessary to establish the potentially protective impact of anti-inflammatory therapy on vascular function in patients with chronic inflammatory diseases.

Effects of Clopidogrel, Prasugrel and Ticagrelor on Microvascular Function and Platelet Reactivity in Patients With Acute Coronary Syndrome Undergoing Coronary Artery Stenting. A Randomized, Blinded, Parallel Group Trial.

Aims: In this pre-specified analysis of the "endothelium, stent and antiplatelet therapy" study, we investigate the impact of antiplatelet therapies on microvascular function in patients undergoing stenting for an acute coronary syndrome. Methods and Results: Fifty-six patients [age: 63(55-67) years, males, 10 diabetics, 27 non-ST-elevation myocardial infarction] were randomized to receive clopidogrel, ticagrelor or prasugrel in form of oral loading 2 h before stenting followed by oral therapy. Investigators were blinded to the allocation. Laser-Doppler microvascular function and ADP-induced platelet aggregation capacity were measured at baseline, 2 h after oral antiplatelet loading, and 1 day, 1 week and 1 month after stenting during chronic therapy with the same antiplatelet agent. Platelet aggregation decreased in all groups 2 h after oral loading, with a significantly larger effect in the prasugrel group (P = 0.009). Similarly, prasugrel and ticagrelor loading was followed by an increase in microvascular reactive hyperemia (P = 0.007 and P = 0.042 compared to clopidogrel). This effect disappeared one day after coronary intervention, with a significant decrease in the prasugrel group (P = 0.026). Similarly, analysis of microvascular conductance showed a larger increase in the prasugrel group 2 h after loading (P = 0.022 among groups), and a decrease in all groups after stenting. Conclusions: Oral loading with prasugrel (and less consistently ticagrelor) is associated with improved microvascular function and stronger platelet inhibition in acute coronary syndrome patients. The microvascular effect was however lost 1 day after stenting and during subsequent follow-up. Further studies are necessary to clarify the the long-term effects and potential benefits of P2Y12 inhibitors on microvascular damage. ClINICALTRIALS.gov N°: NCT01700322 EUDRACT-N°: 2011-005305-73.

"Unlucky punch": unexpected annular rupture during TAVR and successful treatment.

Although rare, annular rupture in TAVR is a feared and often unpredictable complication with relevant impact on in-hospital prognosis. Severe annular calcification is a common risk factor for annular rupture. We report on a case of annular rupture during TAVR with a balloon-expanded prosthesis in the absence of any annular calcification in the planning CT scan and illustrate the proposed pathomechanism as well as its successful immediate surgical management.

The impact of aircraft noise on vascular and cardiac function in relation to noise event number: a randomized trial.

AIMS: Nighttime aircraft noise exposure has been associated with increased risk of hypertension and myocardial infarction, mechanistically linked to sleep disturbance, stress, and endothelial dysfunction. It is unclear, whether the most widely used metric to determine noise exposure, equivalent continuous sound level (Leq), is an adequate indicator of the cardiovascular impact induced by different noise patterns. METHODS AND RESULTS: In a randomized crossover study, we exposed 70 individuals with established cardiovascular disease or increased cardiovascular risk to two aircraft noise scenarios and one control scenario. Polygraphic recordings, echocardiography, and flow-mediated dilation (FMD) were determined for three study nights. The noise patterns consisted of 60 (Noise60) and 120 (Noise120) noise events, respectively, but with comparable Leq, corresponding to a mean value of 45 dB. Mean value of noise during control nights was 37 dB. During the control night, FMD was 10.02 ± 3.75%, compared to 7.27 ± 3.21% for Noise60 nights and 7.21 ± 3.58% for Noise120 nights (P < 0.001). Sleep quality was impaired after noise exposure in both noise scenario nights (P < 0.001). Serial echocardiographic assessment demonstrated an increase in the E/E' ratio, a measure of diastolic function, within the three exposure nights, with a ratio of 6.83 ± 2.26 for the control night, 7.21 ± 2.33 for Noise60 and 7.83 ± 3.07 for Noise120 (P = 0.043). CONCLUSIONS: Nighttime exposure to aircraft noise with similar Leq, but different number of noise events, results in a comparable worsening of vascular function. Adverse effects of nighttime aircraft noise exposure on cardiac function (diastolic dysfunction) seemed stronger the higher number of noise events.

Effects of clopidogrel vs. prasugrel vs. ticagrelor on endothelial function, inflammatory parameters, and platelet function in patients with acute coronary syndrome undergoing coronary artery stenting: a randomized, blinded, parallel study.

AIMS: In a randomized, parallel, blinded study, we investigate the impact of clopidogrel, prasugrel, or ticagrelor on peripheral endothelial function in patients undergoing stenting for an acute coronary syndrome. METHODS AND RESULTS: The primary endpoint of the study was the change in endothelium-dependent flow-mediated dilation (FMD) following stenting. A total of 90 patients (age 62 ± 9 years, 81 males, 22 diabetics, 49 non-ST elevation myocardial infarctions) were enrolled. There were no significant differences among groups in any clinical parameter. Acutely before stenting, all three drugs improved FMD without differences between groups (P = 0.73). Stenting blunted FMD in the clopidogrel and ticagrelor group (both P < 0.01), but not in the prasugrel group. During follow-up, prasugrel was superior to clopidogrel [mean difference 2.13, 95% confidence interval (CI) 0.68-3.58; P = 0.0047] and ticagrelor (mean difference 1.57, 95% CI 0.31-2.83; P = 0.0155), but this difference was limited to patients who received the study therapy 2 h before stenting. Ticagrelor was not significantly superior to clopidogrel (mean difference 0.55, 95% CI -0.73 to 1.82; P = 0.39). No significant differences were seen among groups for low-flow-mediated dilation. Plasma interleukin (IL)-6 (P = 0.02 and P = 0.01, respectively) and platelet aggregation reactivity in response to adenosine diphosphate (P = 0.002 and P = 0.035) were lower in the prasugrel compared to clopidogrel and ticagrelor group. CONCLUSION: As compared to ticagrelor and clopidogrel, therapy with prasugrel in patients undergoing stenting for an acute coronary syndrome is associated with improved endothelial function, stronger platelet inhibition, and reduced IL-6 levels, all of which may have prognostic implications. This effect was lost in patients who received the study medication immediately after stenting. EUDRACT-NO: 2011-005305-73.

Interferon- and ribavirin-free therapy with new direct acting antivirals (DAA) for chronic hepatitis C improves vascular endothelial function.

INTRODUCTION: Chronic Hepatitis C virus infection (HCV) is associated with extrahepatic manifestations and an increased prevalence in cardiovascular disease. New direct acting antivirals (DAA) have revolutionized HCV treatment with high rates of sustained virological response (SVR). Recently it was demonstrated, that SVR reduces morbidity and overall mortality more than can be solely explained by hepatic effects, suggesting that treatment with DAA also affects cardiovascular disease. The aim of this pilot study was to identify possible underlying mechanisms behind the HCV-associated cardiovascular mortality reported by others. METHODS AND RESULTS: 20 HCV patients (10 genotype GT1, 10 GT3) were treated with interferon (IFN)- and ribavirin (RBV)-free DAA regimens for 12 weeks (SVR12). Primary endpoint was an improvement in endothelial function (flow-mediated dilation, FMD) at SVR12 compared to baseline. Patient demographics, FMD, markers for endothelial function and inflammation, coagulation and oxidative stress were measured at baseline, end of treatment and SVR12. All patients achieved SVR12. There was a significant increase in FMD from 9.4 ±â€¯5.2% at baseline to 11.9 ±â€¯4.5% at SVR12 (p = 0.04). Concomitantly, there were significant reductions in levels of endothelium-derived adhesion molecules E-selectin, VCAM-1 and ICAM-1. While APRI values were also significantly lower, liver stiffness did not change significantly. There were no relevant changes in systemic inflammation, oxidative stress, insulin resistance or coagulation pathways. CONCLUSIONS: Successful DAA therapy was associated with improvements in endothelial function and a reduction of soluble adhesion molecules. Our findings indicate that HCV infection affects the endothelium and that DAA-treatment reverses these effects and enhances endothelial function.

[Acute Monkshood Intoxication Requiring Acute Resuscitation in Suicidal Intent]. / Reanimationspflichtige akute Eisenhutintoxikation in suizidaler Absicht.

We report about an acute monkshood intoxication requiring acute resuscitation in suicidal intent in a 56-year-old patient. The Blue Monkshood (Aconitum napellus) is considered to be the most toxic plant in Europe. All plant parts contain the highly toxic alkonoid aconitin. The lethal dose in adults is 2 - 6 mg. Intoxications are often fatal. Asymptomatic patients with suspected monkshood intoxication should also be monitored on an ICU. First signs of intoxication are paraesthesia in the mouth and throat area, abdominal cramps, nausea, vomiting and severe pain in skeletal muscle. Affected patients die within hours after ingestion due to respiratory distress and/or cardiac arrhythmia.The most important measure after oral ingestion is to achieve a rapid primary poison elimination clearance (in the case of awareness clear patients, trigger vomiting, otherwise gastric lavage under protective intubation) and the subsequent carbonation. A specific antidote is not available. The management of an intoxication consists primarily of the therapy of the rhythm disturbances in the form of magnesium and amiodarone.Strict adherence to protective measures (gloves, masks) must be strictly observed. A direct skin contact with plant parts is to be avoided as well as the potential contact with vomit or aspirate.

Twelve-month outcomes after bioresorbable vascular scaffold implantation in patients with acute coronary syndromes. Data from the European Multicenter GHOST-EU Extended Registry.

AIMS: The aim of this study was to report on the midterm outcomes of patients undergoing percutaneous coronary intervention with bioresorbable vascular scaffolds (BVS) for the treatment of acute coronary syndromes (ACS) and compare with those of patients with stable coronary artery disease (sCAD). METHODS AND RESULTS: One thousand four hundred and seventy-seven (1,477) patients underwent implantation of one or more BVS (Absorb BVS; Abbott Vascular, Santa Clara, CA, USA) at 11 European centres and were included in the GHOST-EU registry. Admissions comprised 47.1% of the patients (951 BVS) with ACS, and 52.8% (1,274 BVS) with sCAD. During a median follow-up of 384 (359-460) days, patient-oriented endpoints (PoCE), including all-cause death, any infarction, any revascularisation, were recorded in 271 patients (12-month incidence in ACS patients: 18.5% vs. 11.6% in the sCAD group, p<0.001). Device-oriented composite endpoints (DoCE), cardiac death, target vessel infarction and target lesion revascularisation, were observed in 98 patients (12-month incidence of 4.2% in the sCAD group, 6.4% in the ACS group; p=0.052). The 12-month incidence of definite scaffold thrombosis was 2.6% in ACS patients and 0.8% in XIENCE patients (p=0.006). In multivariate analysis, ACS was a predictor of DoCE (HR: 2.26 [1.34-3.81], p=0.002), PoCE (HR: 1.71 [1.13-2.58], p=0.011), and stent thrombosis (HR: 2.51 [1.13-5.60], p=0.025). In contrast, the incidence of target lesion revascularisation was not different between groups. There was no difference in the incidence of any of these endpoints among the different clinical presentations (unstable angina, non-ST-elevation infarction and ST-elevation infarction). CONCLUSIONS: PoCE, DoCE and scaffold thromboses were more frequent in ACS patients, without any difference among different forms of ACS.

Supervised exercise training in peripheral arterial disease increases vascular shear stress and profunda femoral artery diameter.

Background Arteriogenesis is promoted by flow- and pressure-related forces such as tangential wall stress and laminar shear stress. Exercise training (ET) is known to promote arteriogenesis in peripheral arterial disease (PAD) patients. It remains unclear whether supervised ET (SET) promotes arteriogenesis more efficiently than non-SET (nSET). Methods and results Forty PAD patients participated in a SET or nSET training programme ( n = 20 each) and were compared to 20 healthy individuals without any history of cardiovascular events. Femoral artery diameter, flow and velocity were measured by ultrasound. Tangential wall stress and laminar shear stress were calculated for femoral arteries. Follow-up was performed after a mean of 7.65 ± 1.62 months. At follow-up, only the SET group showed a significant increase in lumen diameter of the profunda femoral artery ( p = 0.03), accompanied by an increase of tangential wall stress ( p = 0.002). Laminar shear stress decreased, but remained higher for the SET group compared to controls ( p < 0.01). Individual changes in walking distance were higher for SET patients ( p = 0.01) than nSET patients ( p = 0.07). Profunda femoral lumen diameter and tangential wall stress correlated directly with walking distance ( r = 0.446; p < 0.001), as well as with each other ( r = 0.743; p < 0.0001). Conclusions Our results indicate that SET promotes arteriogenesis more efficiently than nSET. Femoral lumen diameter and flow might help with the monitoring of ET efficiency and potential arteriogenesis.

Both flow-mediated dilation and constriction are associated with changes in blood flow and shear stress: Two complementary perspectives on endothelial function.

INTRODUCTION: Flow-mediated dilation (FMD) quantifies endothelium-dependent vasomotor responses to short-term increases in blood flow. Low-flow mediated vasoconstriction (L-FMC) has been more recently introduced as additional measure of endothelial function, and its relationship with changes in blood flow, cardiovascular risk factors and FMD ha∧s been less well characterized. MATERIALS AND METHODS: We evaluated radial artery FMD and L-FMC along with the changes in blood flow and shear rate/stress in 584 patients with known or suspected coronary artery disease (72.9% men, mean age 67+/-11 years). Baseline blood flow and shear rate showed a modest association with radial artery FMD and L-FMC (R2 = 0.04 and R2 = 0.02, P < 0.0001). Resting diameter showed a stronger association with FMD but not with L-FMC (R2 = 0.11, P < 0.0001 and R2 = 0.005, P = 0.09). Analysis with generalized additive models showed that age, sex and presence and extent of coronary artery disease were strongly related to both endothelial function measures (P < 0.001 for both), but they explained only 12.4% and 10.1% of the variance in L-FMC and FMD. When the corresponding changes in blood flow were added to these statistical models, the % of variance explained raised to 20.4% and 17.7% for L-FMC and FMD. L-FMC was a strong predictor of FMD even after correction for the changes in blood flow. DISCUSSION: Changes in blood flow are the most important determinants of both L-FMC and FMD. These observations support the concept that both FMD and L-FMC measure endothelium-dependent, shear-induced, vasomotion.

Nighttime aircraft noise impairs endothelial function and increases blood pressure in patients with or at high risk for coronary artery disease.

AIMS: Epidemiological studies suggest the existence of a relationship between aircraft noise exposure and increased risk for myocardial infarction and stroke. Patients with established coronary artery disease and endothelial dysfunction are known to have more future cardiovascular events. We therefore tested the effects of nocturnal aircraft noise on endothelial function in patients with or at high risk for coronary artery disease. METHODS: 60 Patients (50p 1-3 vessels disease; 10p with a high Framingham Score of 23%) were exposed in random and blinded order to aircraft noise and no noise conditions. Noise was simulated in the patients' bedroom and consisted of 60 events during one night. Polygraphy was recorded during study nights, endothelial function (flow-mediated dilation of the brachial artery), questionnaires and blood sampling were performed on the morning after each study night. RESULTS: The mean sound pressure levels L eq(3) measured were 46.9 ± 2.0 dB(A) in the Noise 60 nights and 39.2 ± 3.1 dB(A) in the control nights. Subjective sleep quality was markedly reduced by noise from 5.8 ± 2.0 to 3.7 ± 2.2 (p < 0.001). FMD was significantly reduced (from 9.6 ± 4.3 to 7.9 ± 3.7%; p < 0.001) and systolic blood pressure was increased (from 129.5 ± 16.5 to 133.6 ± 17.9 mmHg; p = 0.030) by noise. The adverse vascular effects of noise were independent from sleep quality and self-reported noise sensitivity. CONCLUSIONS: Nighttime aircraft noise markedly impairs endothelial function in patients with or at risk for cardiovascular disease. These vascular effects appear to be independent from annoyance and attitude towards noise and may explain in part the cardiovascular side effects of nighttime aircraft noise.

Effects of clopidogrel, prasugrel and ticagrelor on endothelial function, inflammatory and oxidative stress parameters and platelet function in patients undergoing coronary artery stenting for an acute coronary syndrome. A randomised, prospective, controlled study.

INTRODUCTION: Particularly in the setting of acute coronary syndromes, the interplay between vascular and platelet function has been postulated to have direct clinical implications. The present trial is designed to test the effect of clopidogrel, prasugrel and ticagrelor on multiple parameters of vascular function, platelet aggregation, oxidative and inflammatory stress before and up to 4 weeks after coronary artery stenting. METHODS AND ANALYSIS: The study is designed as a three-arm, parallel design, randomised, investigator-blinded study. Patients with unstable angina or non-ST elevation myocardial infarction undergoing coronary intervention with a drug-eluting stent will be randomised to receive 600 mg clopidogrel, 60 mg prasugrel or 180 mg ticagrelor followed by oral therapy with the same drug. The primary endpoint of the trial is the impact of antiplatelet treatments on endothelial function as assessed by flow-mediated dilation at 1 day, 1 week and 1 month in patients who have undergone stenting. Secondary endpoints include the impact of study medications on parameters of macrovascular and microvascular function, platelet reactivity, oxidative and inflammatory stress. The study recruitment is currently ongoing and, after an interim analysis which was performed at 50% of the initially planned population, it is planned to continue until July 2015. ETHICS AND DISSEMINATION: The protocol was approved by the local ethics committee. The trial will provide important pathophysiological insight on the relationship between platelet aggregation and endothelial function, two parameters that have been shown to influence patients' prognosis. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01700322; EudraCT-Nr.: 2011-005305-73. Current V.1.3, from 24 February 2014.

Predictive value of brachial reactive hyperemia and flow-mediated dilation in stable coronary artery disease.

BACKGROUND: The purpose of this study was to determine the predictive value of a single measurement of reactive hyperemia (RH) and brachial flow-mediated dilation (FMD) in patients with established stable coronary artery disease (CAD). METHODS: RH and brachial artery FMD were ultrasonographically measured in 325 patients with stable CAD. Patients were followed for cerebro-cardiovascular events. The median follow-up was 3.7 years (range 0.01-5.7 years). RESULTS: Sixty-seven patients (20.6%) had an cerebro-cardiovascular event. Patients with subsequent events had lower FMD (4.9 ± 3.3% versus 6.3 ± 3.5%, p = 0.003), higher brachial artery resting diameter (5.1 ± 0.7 mm versus 4.8 ± 0.7 mm, p = 0.002) and lower NMD (11.2 ± 5.1% versus 12.8 ± 5.4%, p = 0.02), while the mean hyperemic flow velocity and shear stress did not differ from patients without cerebro-cardiovascular events. Cox proportional hazard model adjusted for sex, age, BMI, and traditional cardiovascular risk factors revealed a hazard ratio of 0.84 for lower FMD (p = 0.01). CONCLUSIONS: We conclude that single spot measurements of peak RH do not provide long-term prognostic information, but evaluation of conduit artery FMD predicts long-term cerebro-cardiovascular events in patients with stable CAD. The prognostic value of FMD is incremental to traditional cardiovascular risk factors and may therefore be of clinical importance.

Effect of nighttime aircraft noise exposure on endothelial function and stress hormone release in healthy adults.

AIMS: Aircraft noise disturbs sleep, and long-term exposure has been shown to be associated with increases in the prevalence of hypertension and an overall increased risk for myocardial infarction. The exact mechanisms responsible for these cardiovascular effects remain unclear. METHODS AND RESULTS: We performed a blinded field study in 75 healthy volunteers (mean age 26 years), who were exposed at home, in random order, to one control pattern (no noise) and two different noise scenarios [30 or 60 aircraft noise events per night with an average maximum sound pressure level (SPL) of 60 dB(A)] for one night each. We performed polygraphy during each study night. Noise caused a worsening in sleep quality (P < 0.0001). Noise60, corresponding to equivalent continuous SPLs of 46.3 dB (Leq) and representing environmental noise levels associated with increased cardiovascular events, caused a blunting in FMD (P = 0.016). As well, although a direct comparison among the FMD values in the noise groups (control: 10.4 ± 3.8%; Noise30: 9.7 ± 4.1%; Noise60: 9.5 ± 4.3%, P = 0.052) did not reach significance, a monotone dose-dependent effect of noise level on FMD was shown (P = 0.020). Finally, there was a priming effect of noise, i.e. the blunting in FMD was particularly evident when subjects were exposed first to 30 and then to 60 noise events (P = 0.006). Noise-induced endothelial dysfunction (ED) was reversed by the administration of Vitamin C (P = 0.0171). Morning adrenaline concentration increased from 28.3 ± 10.9 to 33.2 ± 16.6 and 34.1 ± 19.3 ng/L (P = 0.0099). Pulse transit time, reflecting arterial stiffness, was also shorter after exposure to noise (P = 0.003). CONCLUSION: In healthy adults, acute nighttime aircraft noise exposure dose-dependently impairs endothelial function and stimulates adrenaline release. Noise-induced ED may be in part due to increased production in reactive oxygen species and may thus be one mechanism contributing to the observed association of chronic noise exposure with cardiovascular disease.

Lack of evidence for pleiotropic effects of clopidogrel on endothelial function and inflammation in patients with stable coronary artery disease: results of the double-blind, randomized CASSANDRA study.

BACKGROUND: Recently we have demonstrated a dose-dependent improvement of endothelial function after administration of a single loading dose of clopidogrel in patients with coronary artery disease (CAD). We therefore hypothesized that chronic therapy with clopidogrel may improve endothelial function in patients with CAD. METHODS: In a double-blind, randomized, monocentric study 120 patients with established CAD were randomized to one of the following treatment arms: clopidogrel 75 mg q.d., acetylsalicylic acid (ASA) 100 mg q.d., or a combination of ASA and clopidogrel. Endothelium-dependent flow-mediated dilation (FMD) and endothelium-independent nitroglycerin-mediated dilation (NMD) of the brachial artery were determined before and after 28 days of treatment. The effect of clopidogrel was monitored in vitro by ADP-induced platelet aggregation in platelet-rich plasma. Effects of treatment on platelet superoxide production were measured by lucigenin-enhanced chemiluminescence in washed platelets. C-reactive protein, RANTES and monocyte chemoattractant protein-1 were determined as inflammatory markers. The study was registered as ISRCTN34097747. RESULTS: Treatment groups were comparable regarding age, gender, cardiovascular risk factor distribution and concomitant medication. FMD [median (IQR) ASA, +0.8 (-2.0; 2.7); ASA + clopidogrel, ±0 (-2.0; 2.9); clopidogrel, +1.0 (-1.1; 2.4); P = n.s.], NMD, platelet superoxide production or inflammatory markers remained unchanged in all treatment groups. CONCLUSION: We conclude that the beneficial effects of short-term effects of clopidogrel on endothelial function of patients with CAD are abolished after long-term clopidogrel treatment.

Effects of pentaerythritol tetranitrate on endothelial function in coronary artery disease: results of the PENTA study.

BACKGROUND: Pentaerythritol tetranitrate (PETN) differs from other organic nitrates by the lack of tolerance induction and by antioxidative properties. The purpose of this study was to determine the effect of PETN on endothelial function in patients with coronary artery disease (CAD). We hypothesized that the treatment with PETN improves endothelial function in patients with CAD. METHODS: In a prospective, double-blind study, we randomly assigned 80 patients to treatment for 8 weeks with oral PETN 80 mg t.i.d. (PETN) or placebo (C). The primary endpoint was the absolute change in brachial artery flow-mediated dilation (FMD) from baseline to follow-up. Furthermore, changes in nitroglycerin-mediated dilation (NMD), digital peripheral arterial tonometry (PAT) index, vascular shear stress, mean flow velocity, plasma bilirubin, C-reactive protein (CRP) and thiobarbituric acid reactive substances (TBARS), serum ferritin, and the activity of the PETN bioactivating enzyme aldehyde dehydrogenase-2 (ALDH-2) in peripheral blood mononuclear cells were analyzed. Raw data entry, data monitoring and statistical analysis were performed independently. RESULTS: The treatment groups were comparable regarding demographics, cardiovascular risk and concomitant medication. There was no difference in the change in FMD between the two treatment groups (mean +/- SD: PETN: +1.6 +/- 3.3% vs. C: +1.4 +/- 4.1%; P = 0.7). NMD increased after treatment with PETN and was higher compared with C (PETN: +3.8 +/- 5.5% vs. C: +0.6 +/- 4.2%; P = 0.004). Mean PAT index and ALDH-2 activity remained unchanged. Relative changes in mean flow volume (P = 0.04) and mean flow velocity (P = 0.01) upon ischemia increased in the PETN group versus C. Changes in bilirubin, ferritin, TBARS and CRP did not differ between the groups. CONCLUSIONS: We conclude that chronic PETN therapy in patients with CAD may be established for symptomatic treatment without adverse effects on endothelial function and with beneficial effects on the microcirculation.